This invention relates generally to streptogramin antibiotic derivatives, and more particularly, to derivatives of the streptogramin antibiotic virginiamycin M.sub.1, and a process for preparing derivatives of virginiamycin M.sub.1.
The streptogramin family of antibiotics includes the ostreogrycins, vernamycins, synergistins, mikamycins, pristinamycins and virginiamycins. These antibiotics generally occur as mixtures of two different classes of active antibiotic compounds, which are commonly referred to as type A (or M) and type B (or S) antibiotics, respectively. Virginiamycin M.sub.1 is one member of the type A family of streptogramin antibiotics. Type A streptogramin antibiotics show a very strong synergistic effect when mixed with type B streptogramin antibiotics.
Type A antibiotics, such as virginiamycin M (or A), are polyunsaturated cyclic peptolides, which can be considered as highly modified depsipeptides. These compounds generally have a molecular weight of about 500. Type B antibiotics, such as virginiamycin S (or B) are cyclic hexadepsipeptides unrelated in structure to virginiamycin M. These compounds have a molecular weight of about 800. Although each of the A and B types is an active antibiotic in its own right, when mixed together they exhibit marked synergism of activity. Together, these two classes of naturally occurring antibiotics have been widely used for the treatment of human diseases, for numerous veterinary applications, and as agricultural feed additives.
Although the naturally occurring virginiamycin antibiotics have been effective in particularized uses, more widespread use of these beneficial compounds has been hindered due to certain inherent limitations. A principal limitation on the therapeutic use of the virginiamycins is poor water solubility and distribution characteristics. The poor water solubility of these antibiotics means that they can only be administered orally, and that they are not easily distributed to the affected areas of the body.
Another limitation on the use of virginiamycins is that virginiamycins do not easily form conjugates with other therapeutic agents, which hinders the potential formation of new conjugates having improved and wider ranges of biological activities.
Yet another limitation on the use of these naturally occurring virginiamycins is that it is difficult to attach reactive groups such as affinity labels to the type A antibiotics such as virginiamycin, and at the same time retain the normal antibiotic activity. The ability to attach such groups would allow further study of the mechanism of the antibiotic activity, in order to provide researchers with information that could be used to improve the effectiveness of the antibiotic, to synthesize improved drugs, or to study the structure and function of ribosomes, which are the natural target of these antibiotics.
Although certain derivatives of virginiamycin have been formulated in the past, many of the known derivatives have exhibited a loss of antibacterial activity when compared to the virginiamycin. Although some derivatives have retained a certain level of activity, these derivatives often do not possess a conveniently reactive functional group that can be used for attaching other agents to the antibiotic. The most active derivatives have been obtained by addition of amino-containing thiols to virginiamycin M.sub.1, followed by oxidation of the resulting sulfide linkages to sulfoxides and sulfones, and conversion of the amine functions to ammonium salts. Some of these compounds exhibit useful antibacterial activity. A review article by Paris, et al, summarizes much of this work. Paris, et al., "The Chemistry of Pristinamycins", Recent Progress in the Chemical Synthesis of Antibiotics, 1990, pp. 183-247.
Prior work by one of the present inventors has demonstrated the use of N-hydroxysuccinimide ester (HSE) as an affinity label with virginiamycin S.sub.1 (VS) (U.S. Pat. No. 5,200,394). In this work, the HSE affinity label was activated for binding to ribosomal proteins at 30.degree. C., or permissive conditions. However, such work has not heretofore been successfully employed with virginiamycin M.sub.1.
It is desired to provide derivatives of the type A virginiamycin antibiotics having antibiotic activity comparable to the antibiotic activity of the natural virginiamycin. It is further desired to provide such derivatives wherein the solubility and distribution characteristics are improved over the original antibiotic, that are adaptable for inclusion of affinity labels, and that may be conjugated with other therapeutic agents.